https://www.nature.com/articles/d41586-024-00930-y Skip to main content Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Advertisement Advertisement Nature * View all journals * Search * Log in * Explore content * About the journal * Publish with us * Subscribe * Sign up for alerts * RSS feed 1. nature 2. news 3. article * NEWS * 27 March 2024 * Correction 27 March 2024 Memories are made by breaking DNA -- and fixing it Nerve cells form long-term memories with the help of an inflammatory response, study in mice finds. By * Max Kozlov 1. Max Kozlov View author publications You can also search for this author in PubMed Google Scholar * Twitter * Facebook * Email SEM (Scanning Electron Micrograph) of human brain cells showing an extensive network of interconnecting dendrites. Neurons (shown here in a coloured scanning electron micrograph) mend broken DNA during memory formation. Credit: Ted Kinsman/Science Photo Library When a long-term memory forms, some brain cells experience a rush of electrical activity so strong that it snaps their DNA. Then, an inflammatory response kicks in, repairing this damage and helping to cement the memory, a study in mice shows. The findings, published on 27 March in Nature^1, are "extremely exciting", says Li-Huei Tsai, a neurobiologist at the Massachusetts Institute of Technology in Cambridge who was not involved in the work. They contribute to the picture that forming memories is a "risky business", she says. Normally, breaks in both strands of the double helix DNA molecule are associated with diseases including cancer. But in this case, the DNA damage-and-repair cycle offers one explanation for how memories might form and last. It also suggests a tantalizing possibility: this cycle might be faulty in people with neurodegenerative diseases such as Alzheimer's, causing a build-up of errors in a neuron's DNA, says study co-author Jelena Radulovic, a neuroscientist at the Albert Einstein College of Medicine in New York City. Inflammatory response This isn't the first time that DNA damage has been associated with memory. In 2021, Tsai and her colleagues showed that double-stranded DNA breaks are widespread in the brain, and linked them with learning ^2. To better understand the part these DNA breaks play in memory formation, Radulovic and her colleagues trained mice to associate a small electrical shock with a new environment, so that when the animals were once again put into that environment, they would 'remember' the experience and show signs of fear, such as freezing in place. Then the researchers examined gene activity in neurons in a brain area key to memory -- the hippocampus. They found that some genes responsible for inflammation were active in a set of neurons four days after training. Three weeks after training, the same genes were much less active. [d41586-024] How to see a memory The team pinpointed the cause of the inflammation: a protein called TLR9, which triggers an immune response to DNA fragments floating around the insides of cells. This inflammatory response is similar to one that immune cells use when they defend against genetic material from invading pathogens, Radulovic says. However, in this case, the nerve cells were responding not to invaders, but to their own DNA, the researchers found. TLR9 was most active in a subset of hippocampal neurons in which DNA breaks resisted repair. In these cells, DNA repair machinery accumulated in an organelle called the centrosome, which is often associated with cell division and differentiation. However, mature neurons don't divide, Radulovic says, so it is surprising to see centrosomes participating in DNA repair. She wonders whether memories form through a mechanism that is similar to how immune cells become attuned to foreign substances that they encounter. In other words, during damage-and-repair cycles, neurons might encode information about the memory-formation event that triggered the DNA breaks, she says. When the researchers deleted the gene encoding the TLR9 protein from mice, the animals had trouble recalling long-term memories about their training: they froze much less often when placed into the environment where they had previously been shocked than did mice that had the gene intact. These findings suggest that "we are using our own DNA as a signalling system" to "retain information over a long time", Radulovic says. Fitting in How the team's findings fit with other discoveries about memory formation is still unclear. For instance, researchers have shown that a subset of hippocampal neurons known as an engram are key to memory formation^3. These cells can be thought of as a physical trace of a single memory, and they express certain genes after a learning event. But the group of neurons in which Radulovic and her colleagues observed the memory-related inflammation are mostly different from the engram neurons, the authors say. [d41586-024] Flashes of light show how memories are made Tomas Ryan, an engram neuroscientist at Trinity College Dublin, says the study provides "the best evidence so far that DNA repair is important for memory". But he questions whether the neurons encode something distinct from the engram -- instead, he says, the DNA damage and repair could be a consequence of engram creation. "Forming an engram is a high-impact event; you have to do a lot of housekeeping after," he says. Tsai hopes that future research will address how the double-stranded DNA breaks happen and whether they occur in other brain regions, too. Clara Ortega de San Luis, a neuroscientist who works with Ryan at Trinity College Dublin, says that these results bring much-needed attention to mechanisms of memory formation and persistence inside cells. "We know a lot about connectivity" between neurons "and neural plasticity, but not nearly as much about what happens inside neurons", she says. doi: https://doi.org/10.1038/d41586-024-00930-y Read the related News & Views: 'Innate immunity in neurons makes memories persist'. Updates & Corrections * Correction 27 March 2024: An earlier version of this story indicated that broken DNA accumulated in the centrosome. It is DNA repair machinery that accumulates in that organelle. References 1. Jovasevic, V. et al. Nature 628, 145-153 (2024). Article Google Scholar 2. Stott, R. T., Kritsky, O. & Tsai, L.-H. PLoS ONE 16, e0249691 (2021). Article PubMed Google Scholar 3. Josselyn, S. A. & Tonegawa, S. Science 367, eaaw4325 (2020). Article Google Scholar Download references Reprints and permissions Related Articles * [d41586-024] Flashes of light show how memories are made * [d41586-024] How to see a memory * [d41586-024] Anti-ageing protein injection boosts monkeys' memories * [d41586-024] The brain cells linked to protection against dementia Subjects * Neuroscience * Brain Latest on: Neuroscience Innate immunity in neurons makes memories persist Innate immunity in neurons makes memories persist News & Views 27 MAR 24 Formation of memory assemblies through the DNA-sensing TLR9 pathway Formation of memory assemblies through the DNA-sensing TLR9 pathway Article 27 MAR 24 A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure Article 27 MAR 24 Brain Innate immunity in neurons makes memories persist Innate immunity in neurons makes memories persist News & Views 27 MAR 24 Ketamine is in the spotlight thanks to Elon Musk -- but is it the right treatment for depression? 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